1. Filed of the Invention
This invention is directed to modified ether glyceroglycolipids, compositions containing these compounds, and to the therapeutic administration of these compounds and compositions to animals, including those afflicted with cancers, as well as various other diseases and disorders.
2. Background of the Invention
Etherlipids are amphipathic lipids with ether linkages connecting their hydrocarbons with their molecular backbones, and are synthetic analogs of platelet activating factor (xe2x80x9cPAFxe2x80x9d; 1-O-2-acetyl-sn-glycero-3-phosphocholine). PAF is an effector believed to be involved in a variety of physiological processes, such as inflammation, immune responses and allergic reactions.
Etherlipids can accumulate in cell membranes, following which the lipids may affect the cells in a number of ways. Cell membrane accumulation can lead to disturbance of membrane lipid organization by a detergent-like activity of etherlipids; membrane structure, and hence, cell stability, can be disrupted by this activity. Phospholipid metabolism can also be disrupted, as the activities of several of the enzymes involved, e.g., CTP: phosphocholine cytidyl transterase, diacylglycerol kinase, sodium/potassium adenosine triphosphate phosphatase, acyl transferases, lysophospholipase, and phospholipases C and D, are inhibited in the presence of etherlipids. Etherlipids can also affect transmembrane signaling pathways, nutrient uptake, cellular differentiation and apoptosis.
Moreover, etherlipids are believed to be cytotoxic to cancer cells, and have been shown to be effective anticancer agents in animals (see, for example, Lohmeyer and Bittman, 1994; Lu et al. (1994a); Lu et al. (1994b); Dietzfelbinger et al. (1993); Zeisig et al. (1993); Berdel (1991); Workman (1991); Workman et al. (1991); Bazill and Dexter (1990); Berdel (1990); Guivisdalsky et al. (1990a); Guivisdalsky et al. (1990b); Powis et al. (1990); Layton et al. (1980): Great Britain Patent No. 1,583,661; U.S. Pat. No. 3,752,886). However, etherlipids are generally not toxic to normal cells. Ether lipids"" ability to act selectively on cancer cells is believed to be due to the cancer cells"" lack of the alkyl cleavage enzymes necessary for hydrolysis of the lipids; the resulting intracellular lipid accumulation can disrupt the cells"" functioning in a variety of ways. Normal cells typically possess these enzymes, and hence, to prevent their intracellular accumulation.
However, not all normal cells contain sufficient levels of alkyl cleavage enzymes to prevent intracellular ether lipid accumulation; cells which do not possess the requisite levels of the enzymes can be subject to the same disruptive effects of ether lipid action as are cancer cells. Red blood cells, for example, lack the requisite alkyl cleavage enzymes, and hence, are also subject to a detergent-like activity of ether lipids. Hemolysis which results from exposure of these cells to ether lipidis having detergent-like activity can be a major drawback to therapeutic use of the ether lipids (see, for example, Houlihan et al., 1995).
A number of different approaches are potentially available for decreasing or eliminating such drug-induced toxicity. One such approach is to incorporate the drugs into lipid-based carriers, e.g., liposomes. Such carriers can buffer drug toxicity, for example, by sequestering the drug in the carrier such that the drug is unavailable for inducing toxicity. Lipid carriers ran also buffer drug-induced toxicity by interacting with the drug such that the drug is then itself unable to interact with the cellular targets through which it exerts its cytotoxic effects. The carriers also maintain the ability of the drugs to be therapeutically effective when released therefrom, e.g., when the carriers are broken down in the vicinity of tumors.
This invention provides etherdipids in which the lipids"" phosphate-based headgroups have been replaced with sugar moieties, the sugars themselves having been modified by substitution of one or more of their hydroxyl groups; applicants have found that such modification of etherlipids affords the modified etherlipids beneficial anticancer activity. Certain etherlipid analogues have been mentioned in the art, including O- and S-linked glucose and maltose substitutions of edelfosine""s phosphoryicholine group. However, none of these analogues contain sugars modified by replacement of one or more hydroxyl groups.
Etherlipids of this invention are amphipathic lipid molecules comprising a polyol backbone, a hydrocarbon chain, a methyl group and a modified sugar moiety. The ether lipids have the following structural formula: 
The hydrocarbon, attached to the polyol by way of an ether linkage, is designated herein as xe2x80x9cR1xe2x80x9d and is a group having the formula Y1Y2, wherein Y1 is the group xe2x80x94(CH2)n1((CHxe2x95x90CH)n2(CH2)n3(CHxe2x95x90CH)n4(CH2)n5(CHxe2x95x90CH)n6(CH2)n7(CHxe2x95x90CH)n8(CH2)n9xe2x80x94 and Y2 is CH3, CO2H or OH. Preferably, the hydrocarbon is saturated and Y1 is xe2x80x94C(O)(CH2)n1; Y2 is preferably CH3. Most preferably, presently, the hydrocarbon is xe2x80x94C(O)(CH2)16CH3. The methyl group is attached to the polyol by way of a linkage, designated herein as xe2x80x9cR2 which is O, S, NH, or xe2x80x94NHC(O)xe2x80x94. Most preferably, R2 is O; accordingly, this invention""s glycerol-based etherlipids preferably have a methoxy group at the sn-2 position. The modified sugar attached to the polyol, and designated herein as xe2x80x9cR3xe2x80x9d, has the following formula: 
wherein X2, X3, X4, X5, X6 and X7 are either H, OH or a substitution for one of these groups. No more than two of X2, X3, X4, X5 X6 and X7 are OH, and no more than two of X2/X3, X4/X5 and X6/X7 are H/OH or OH/H, when X8 is CH2OH, i.e., when a group other than the OH at C-6 is modified. No more than three of X2, X3, X4, X5X6 and X7 are OH, and no more than three of X2/X3, X4/X5 and X6/X7 are H/OH or OH/H, when X8 is the group xe2x80x94COOX10.
Etherlipids are known to be effective anticancer agents, and can also exert beneficial therapeutic activity against a variety of other diseases and disorders, such as those characterized by inflammation and by microbial infection. Moreover, etherlipids are relatively inactive towards most normal cells. This ability of etherlipids to be selectively cytotoxic to particular target cells is believed to be due to the target cells"" lack of the alkyl cleavage enzymes required for hydrolysis of the lipids: normal cells typically possess sufficient levels of these enzymes to prevent intracellular ethedipid accumulation, while cancer cells generally do not. However, some normal cells, e.g., red blood cells, do not possess the requisite alkyl cleavage enzymes in sufficient quantities to prevent etherlipids from accumulating therein to toxic levels; accordingly, ethehipids can be cytotoxic to such cells as well. Etherlipids are incorporated into lipid-based carriers herein such that the etherlipids cannot then be exchanged into cell membranes. Nevertheless, the etherlipids are maintained in a therapeutically effective form within the carrier, and when released therefrom, can act against their intended targets.